Cancer Gene Discovery to Identify Targetable Targets

癌症基因发现以确定可靶向的靶点

• 批准号: 9321279
• 负责人: CARLO M CROCE
• 金额: $ 92.4万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-11 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321279
• 关键词: 13q14; Affect; Apoptosis; Award; BCL-2 Protein; BCL2 gene; Binding; Burkitt Lymphoma; Cachexia; Cells; Chromatin Structure; Chromosomes; Code; DNA Sequence Alteration; Dendritic Cells; Disease; Endosomes; Follicular Lymphoma; Gene Family; Gene Mutation; Genes; Germ-Line Mutation; Homologous Gene; Human; Human Genome; IL6 gene; Immunoglobulins; In complete remission; Journals; Knockout Mice; MLL gene; MYC gene; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; MicroRNAs; Mus; Mutation; Myoblasts; Oncogenes; Pathogenesis; Pathway interactions; Patients; Peer Review; Pharmaceutical Preparations; Proteins; Publishing; Research Personnel; Role; Scientist; Somatic Mutation; T-Cell Leukemia; T-Cell Receptor; T-Lymphocyte; TLR8 gene; Transgenic Mice; Tumor Suppressor Genes; Untranslated RNA; Work; cancer genetics; gene discovery; indexing; macrophage; microvesicles; novel; programs; prototype; public health relevance; receptor; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): Previously, I was awarded the Outstanding Investigator award for two terms before the Program at NCI was discontinued. I have continued to be extremely productive to these days. My H index is 179 and I am one of the most cited scientists in the world. I have published more than 1000 articles in peer reviewed journals. I have also made many important discoveries in cancer genetics and have identified and characterized many cancer genes. My discoveries that changed the ways to think about cancer, I believe, are: the demonstration of the juxtaposition of the MYC oncogene to the immunoglobulin loci and its dysregulation in Burkitt lymphoma, the first demonstration of the specific gene alterations in human cancer. The discovery of the BCL2 gene and its involvement in follicular lymphoma and in other malignancies. The Bcl2 protein is now targeted by ABT199, a drug of Abbott that causes complete remission in patients with CLL. BCL2 is the prototype of a large family of genes that control programmed cell death, or apoptosis. The discovery of ALL1, now renamed MLL1, a gene involved in more than 50 different translocations in ALL and AML. Its dysregulation in cancer affects chromatin structure. I also discovered the partial duplication of ALL1 (MLL1) in AML. I also discovered TCL1, which is responsible for 98% of human pre T cell leukemias, and that this gene is dysregulated in most of the aggressive CLLs. I have also discovered the role of translocations involving the T cell receptor in T cell malignancies. I also generated transgenic and KO mice to validate the oncogenes and tumor suppressor genes we discovered. It was thought that all cancer genes were encoding protein products. The dogma was that only protein coding genes that represent only 2% of the human genome were important and the remaining 98% was "junk". This view was shattered by my discovery in 2002 that CLL is caused by the loss of two microRNA genes on chromosome 13q14, miR-15a and miR-16-1. Thus genes encoding non coding RNAs can also be involved in cancer pathogenesis. We also found that these two microRNAs target BCL2, the gene I discovered in 1984. We also discovered germline and somatic mutations in microRNA genes in human malignancies and that microRNAs are dysregulated in all cancers, primarily because several of them are downstream targets of pathways responsible for oncogenesis. More recently, we discovered that tumors such as lung cancer and pancreatic cancer secrete microvesicles that fuse with macrophages and dendritic cells. MiR-21 that is contained in such microvesicles is internalized, reaches the endosomes of the recipient cells and binds and activates Toll Like Receptor 8 in humans and 7 (it's homologue) in the mouse, activating the receptor. Then NF-κB is activated and IL6 and TNFalpha are secreted, facilitating tumor spreading and metastatic disease. This year we showed that fusion of microvesicles with myoblasts causes cachexia.

 描述（由申请人提供）： 此前，在 NCI 项目终止之前，我曾获得过两个学期的杰出研究者奖。直到现在我的工作效率仍然非常高。我的 H 指数是 179，我是世界上被引用次数最多的科学家之一。我已在同行评审期刊上发表了 1000 多篇文章。 我还在癌症遗传学方面取得了许多重要发现，并鉴定和表征了许多癌症基因。我相信，我的发现改变了人们对癌症的看法：在伯基特淋巴瘤中证明了 MYC 癌基因与免疫球蛋白基因座的并置及其失调，这是人类癌症中特定基因改变的首次证明。 BCL2 基因的发现及其与滤泡性淋巴瘤和其他恶性肿瘤的关系。 Bcl2 蛋白现在是 ABT199 的靶标，ABT199 是雅培公司的一种药物，可以使 CLL 患者完全缓解。 BCL2 是控制程序性细胞死亡或细胞凋亡的一大基因家族的原型。 ALL1 的发现，现已更名为 MLL1，该基因参与 ALL 和 AML 中 50 多种不同的易位。它在癌症中的失调会影响染色质结构。我还发现了 AML 中 ALL1 (MLL1) 的部分重复。我还发现了 TCL1，它与 98% 的人类前 T 细胞白血病有关，并且该基因在大多数侵袭性 CLL 中失调。我还发现了涉及 T 细胞受体的易位在 T 细胞恶性肿瘤中的作用。我还生成了转基因小鼠和 KO 小鼠来验证我们发现的癌基因和抑癌基因。 人们认为所有癌症基因都编码蛋白质产物。人们的教条是，只有占人类基因组 2% 的蛋白质编码基因才是重要的，其余 98% 都是“垃圾”。 2002 年，我发现 CLL 是由染色体 13q14 上两个 microRNA 基因 miR-15a 和 miR-16-1 的缺失引起的，这一观点被打破了。因此，编码非编码RNA的基因也可能参与癌症发病机制。我们还发现这两种 microRNA 靶向 BCL2，这是我在 1984 年发现的基因。我们还发现了人类恶性肿瘤中 microRNA 基因的种系和体细胞突变，并且 microRNA 在所有癌症中失调，主要是因为其中一些是负责肿瘤发生的途径的下游靶标。最近，我们发现肺癌和胰腺癌等肿瘤会分泌与巨噬细胞和树突状细胞融合的微泡。此类微泡中包含的 MiR-21 被内化，到达受体细胞的内体，并结合并激活人类中的 Toll 样受体 8 和小鼠中的 Toll 样受体 7（其同源物），从而激活受体。然后NF-κB被激活并分泌IL6和TNFα，促进肿瘤扩散和转移。今年，我们发现微泡与成肌细胞的融合会导致恶病质。